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Long bone ecomorphology has proven effective for paleohabitat reconstructions across a wide range of mammalian clades. Still, there is no comprehensive framework to allow interpretation of long bone morphological variation within and between different monophyletic groups. Here, we investigated the use of humerus morphometry to classify living members of the orders Carnivora and ungulates based on their preferred habitats. Using geometric morphometrics, we extracted three different kinds of humerus shape data describing interspecific variation with and without accounting for evolutionary allometry and phylogenetic signal. The traditional a priori categorization of species in open, mixed, and closed habitats was employed in combination with selected subsets of shape variables to identify the best-predictive models for habitat adaptation. These were identified based on the statistical performance of phylogenetic and non-phylogenetic discriminant analyses and then applied to predict habitats on a subsample of fossil species. Size-free shape data combined with phylogenetic discriminant analyses showed the highest rate of accuracy in habitat classification for a combined sample of carnivorans and ungulates. Conversely, when the two groups were investigated separately, traditional shape data analyzed with phylogenetic discriminant function analyses provided models with the greatest predictive power. By combining carnivorans and ungulates within the same methodological framework we identified common adaptive features in closed habitat-adapted species that show compressed epiphyses, while open habitat-adapted species have expanded epiphyses. These morphologies evolved to allow significant degree of direction switches during locomotion in closed habitats compared to open habitat-adapted species whose forelimb joints evolved to stabilize articulations for increasing speed., (© 2024 The Author(s). The Anatomical Record published by Wiley Periodicals LLC on behalf of American Association for Anatomy.)

Researchers have developed numerous individual differences measures to assess people's endorsement of honor ideology (i.e., beliefs regarding the importance of honor and reputation) with most ranging from 12-36 items in length. Despite having great utility, the length of these measures magnifies the costs associated with survey research, especially in research contexts that use large, representative samples (e.g., health surveys). The present study aimed to develop and validate single-item measures that assess participants' agreement with gender-specific honor prototypes, as well as short-form versions of the honor ideology for manhood (HIM) and honor ideology for womanhood (HIW) scales. An initial sample of participants ( N  = 879) completed single-item honor prototype measures, a battery of previously validated honor measures (including the HIM and HIW), and measures of constructs previously shown to be related to the dynamics of honor (e.g., aggression, firearm ownership). A second sample of participants ( N  = 100) completed the new measures, as well as an abbreviated battery of honor measures, to examine test-retest reliability. Results indicated that the new, brief measures were strongly correlated with both the original HIM and HIW as well as several other established honor measures. Moreover, the associations between these new measures and honor-related outcomes were nearly identical to those found with the original HIM and HIW. Our new measures also demonstrated acceptable test-retest reliability, despite being single-item scales. Overall, the present work provides preliminary support for several brief measures of honor endorsement that researchers can use when longer scales are not feasible.

Objectives: This pilot study evaluated the feasibility of a live, interactive, synchronous, online, manualized intervention, Breath-Body-Mind Introductory Course (BBM-IC), for medical students. BBM-IC includes breathing, movement, and attention-focus techniques for stress management and better emotion regulation, energy, sleep, and mental focus., Methods: Medical students attending a 2-h BBM demonstration were invited to participate in the 12-h BBM-IC and weekly 45-min 6-week group practice. Measures were obtained using Survey Monkey: patient health questionnaire (PHQ9), generalized anxiety disorder-7 (GAD-7), exercise-induced feeling inventory (EFI), sleep quality scale (SQS), and body perception questionnaire-short form (BPQ-SF) at pre-BBM-IC (T1), post-BBM-IC (T2), and 6 weeks post (T3). Perceived stress scale (PSS) and meditation practices questionnaire (MPQ) were measured at baseline (T1) only., Results: Twelve medical students participated in BBM-IC 4-h daily for 3 days. Six attended practice sessions and completed 6-week post-tests. Mean scores comparison identified two variable sets with significant improvements: EFI tranquility ( p  < .005) and supradiaphragmatic reactivity ( p  < .040). Two measures reached near significance: SQS ( p  ≤ .060) and PHQ9 ( p  ≤ .078)., Conclusion: This pilot study provided preliminary evidence that BBM-IC may reduce stress and anxiety symptoms while improving mood, energy, mental focus, and other correlates of psychophysiological state in medical students. Taking time for self-care is challenging for medical students, as reflected in the small study enrollment. Designating time for BBM as a requirement within the medical curriculum would probably enable more students to participate and acquire skills to reduce the effects of stress on their physical and psychological health, as well as the health of their patients., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

The lizard Teira dugesii exhibits morphological divergence between beach and inland habitats in the face of gene flow, within the volcanic island of Madeira, Portugal. Here, we analyzed genomic data obtained by genotyping-by-sequencing, which provided 16,378 single nucleotide polymorphisms (SNPs) from 94 individuals sampled from 15 sites across Madeira. Ancient within-island divergence in allopatry appears to have mediated divergence in similar species within other Atlantic islands, but this hypothesis was not supported for T. dugesii. Across all samples, a total of 168 SNPs were classified as statistical outliers using pcadapt and OutFLANK. Redundancy analysis (RDA) revealed that 17 of these outliers were associated with beach/inland habitats. The SNPs were located within 16 sequence tags and 15 of these were homologous with sequences in a 31 Mb region on chromosome 3 of a reference wall lizard genome (the remaining tag could not be associated with any chromosome). We further investigated outliers through contingency analyses of allele frequencies at each of four pairs of adjacent beach-inland sites. The majority of the outliers detected by the RDA were confirmed at two pairs of these matched sites. These analyses also suggested some parallel divergence at different localities. Six other outliers were associated with site elevation, four of which were located on chromosome 5 of the reference genome. Our study lends support to a previous hypothesis that divergent selection between gray shingle beaches and inland regions overcomes gene flow and leads to the observed morphological divergence between populations in these adjacent habitats., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Introduction: Veteran total and firearm suicide rates are higher compared to the general population. Among the general population, total and firearm suicide rates are higher in US states deemed cultures of honor compared to non-honor states, likely because honor states have higher firearm ownership rates and fewer firearm laws. Considering that veterans tend to live in states with fewer firearm laws and that veteran population rates predict both statewide total and firearm suicide rates, it is possible that the elevated suicide rates seen in honor states in part due to those states having a greater presence of veterans compared to non-honor states., Method: Publicly available databases were used to obtain total and firearm suicide rates (per 100 k) for veterans and non-veterans, as well as our covariates (e.g., rurality)., Results: Veteran population proportions were higher in honor states than non-honor states. Veteran and non-veteran total and firearm suicide rates were higher in honor states compared to non-honor states. Statewide differences in all four suicide rates were indirectly explained by honor states having higher firearm ownership than non-honor states., Conclusions: These findings add to a growing body of literature showing that enacting firearm regulations may be a viable public health approach for preventing suicide., (© 2023 American Association of Suicidology.)

Populations on the edge of a species' distribution may represent an important source of adaptive diversity, yet these populations tend to be more fragmented and are more likely to be geographically isolated. Lack of genetic exchanges between such populations, due to barriers to animal movement, can not only compromise adaptive potential but also lead to the fixation of deleterious alleles. The south-eastern edge of chimpanzee distribution is particularly fragmented, and conflicting hypotheses have been proposed about population connectivity and viability. To address this uncertainty, we generated both mitochondrial and MiSeq-based microsatellite genotypes for 290 individuals ranging across western Tanzania. While shared mitochondrial haplotypes confirmed historical gene flow, our microsatellite analyses revealed two distinct clusters, suggesting two populations currently isolated from one another. However, we found evidence of high levels of gene flow maintained within each of these clusters, one of which covers an 18,000 km 2 ecosystem. Landscape genetic analyses confirmed the presence of barriers to gene flow with rivers and bare habitats highly restricting chimpanzee movement. Our study demonstrates how advances in sequencing technologies, combined with the development of landscape genetics approaches, can resolve ambiguities in the genetic history of critical populations and better inform conservation efforts of endangered species., (© 2023 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

Background: During the COVID-19 pandemic, healthcare workers endured prolonged stress affecting their psychological well-being. Objectives: (1) Evaluate the effects of the Breath-Body-Mind Introductory Course (BBMIC) on COVID-related stress among employees of the Regional Integrated Support for Education, Northern Ireland, (2) Reduce the risk of adverse effects from COVID-related stress, and (3) Evaluate the effects of BBMIC on indicators of psychophysiological states and the consistency with hypothesized mechanisms of action., Methods: In this single group study, a convenience sample of 39 female healthcare workers completed informed consent and baseline measures: Perceived Stress Scale (PSS), Stress Overload Scale-Short (SOS-S), and Exercise-Induced Feelings Inventory (EFI). Following the online BBMIC 4 h/day for 3 days and the 6 week solo (20 min/day) and group practice (45 min weekly), repeat testing plus the Indicators of Psychophysiological State (IPSS) and Program Evaluation were obtained., Results: Baseline (T1) mean PSS score was significantly elevated compared to a normative sample: PSS = 18.2 vs. 13.7 ( p  < 0.001) and improved significantly 11 weeks post-BBMIC (T4). SOS-S mean score declined from 10.7(T1) to 9.7 at 6 week post-test (T3). The SOS-S proportion of High Risk scores found in 22/29 participants (T1), dropped to 7/29 (T3). EFI mean subscale scores improved significantly from T1 to T2 and T3 for Revitalization ( p  < 0.001); Exhaustion ( p  < 0.002); and Tranquility ( p  < 0.001); but not Engagement ( p  < 0.289)., Conclusion: Among RISE NI healthcare workers affected by COVID-related stress, participation in the BBMIC significantly reduced scores for Perceived Stress, Stress Overload, and Exhaustion. EFI Revitalization and Tranquility scores significantly improved. More than 60% of participants reported moderate to very strong improvements in 22 indicators of psychophysiological state, e.g., tension, mood, sleep, mental focus, anger, connectedness, awareness, hopefulness, and empathy. These results are consistent with the hypothesized mechanisms of action whereby voluntarily regulated breathing exercises change interoceptive messaging to brain regulatory networks that shift psychophysiological states of distress and defense to states of calmness and connection. These positive findings warrant validation in larger, controlled studies to extend the understanding of how breath-centered Mind-body Medicine practices could mitigate adverse effects of stress., Competing Interests: PG and RB have written books and book chapters about Complementary and Integrative Medicine, including breath-centered mind-body practices. They sometimes receive financial remuneration or honoraria for teaching mind-body practices. They are Co-Founders and members of the Board of Directors of the Breath-Body-Mind Foundation, a not-for-profit 501(c)3 that provides pro bono crisis relief programs for survivors of mass disasters, scholarships for applicants who cannot afford to pay for training, and grants for research projects. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gerbarg, Dickson, Conte and Brown.)

Background: Opioid use disorder (OUD) contributes to rising morbidity and mortality. Life-saving OUD treatments can be provided in primary care but most patients with OUD don't receive treatment. Comorbid depression and other conditions complicate OUD management, especially in primary care. The MI-CARE trial is a pragmatic randomized encouragement (Zelen) trial testing whether offering collaborative care (CC) to patients with OUD and clinically-significant depressive symptoms increases OUD medication treatment with buprenorphine and improves depression outcomes compared to usual care., Methods: Adult primary care patients with OUD and depressive symptoms (n ≥ 800) from two statewide health systems: Kaiser Permanente Washington and Indiana University Health are identified with computer algorithms from electronic Health record (EHR) data and automatically enrolled. A random sub-sample (50%) of eligible patients is offered the MI-CARE intervention: a 12-month nurse-driven CC intervention that includes motivational interviewing and behavioral activation. The remaining 50% of the study cohort comprise the usual care comparison group and is never contacted. The primary outcome is days of buprenorphine treatment provided during the intervention period. The powered secondary outcome is change in Patient Health Questionnaire (PHQ)-9 depression scores. Both outcomes are obtained from secondary electronic healthcare sources and compared in "intent-to-treat" analyses., Conclusion: MI-CARE addresses the need for rigorous encouragement trials to evaluate benefits of offering CC to generalizable samples of patients with OUD and mental health conditions identified from EHRs, as they would be in practice, and comparing outcomes to usual primary care. We describe the design and implementation of the trial, currently underway., Trial Registration: ClinicalTrials.gov Identifier: NCT05122676. Clinical trial registration date: November 17, 2021., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Limited spatial separation within small islands suggests that observed population divergence may occur due to habitat differences without interruption to gene flow but strong evidence of this is scarce. The wall lizard Teira dugesii lives in starkly contrasting shingle beach and inland habitats on the island of Madeira. We used a matched pairs sampling design to examine morphological and genomic divergence between four beach and adjacent (<1 km) inland areas. Beach populations are significantly darker than corresponding inland populations. Geometric morphometric analyses reveal divergence in head morphology: beach lizards have generally wider snouts. Genotyping-by-sequencing allows the rejection of the hypothesis that beach populations form a distinct lineage. Bayesian analyses provide strong support for models that incorporate gene flow, relative to those that do not, replicated at all pairs of matched sites. Madeiran lizards show morphological divergence between habitats in the face of gene flow, revealing how divergence may originate within small islands., (© 2023. The Author(s).)

Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with complex human traits, but only a fraction of variants identified in discovery studies achieve significance in replication studies. Replication in genome-wide association studies has been well-studied in the context of Winner's Curse, which is the inflation of effect size estimates for significant variants due to statistical chance. However, Winner's Curse is often not sufficient to explain lack of replication. Another reason why studies fail to replicate is that there are fundamental differences between the discovery and replication studies. A confounding factor can create the appearance of a significant finding while actually being an artifact that will not replicate in future studies. We propose a statistical framework that utilizes genome-wide association studies and replication studies to jointly model Winner's Curse and study-specific heterogeneity due to confounding factors. We apply this framework to 100 genome-wide association studies from the Human Genome-Wide Association Studies Catalog and observe that there is a large range in the level of estimated confounding. We demonstrate how this framework can be used to distinguish when studies fail to replicate due to statistical noise and when they fail due to confounding., (© The Author(s) 2022. Published by Oxford University Press on behalf of Genetics Society of America.)

Narwhals and belugas are toothed whales belonging to the Monodontidae. Belugas have a circumpolar Arctic and sub-Artic distribution while narwhals are restricted to the Atlantic Arctic. Their geographical ranges overlap during winter migrations in the Baffin Bay area (Canada/West Greenland) and successful interbreeding may occur. Here, we employed geometric morphometrics on museum specimens to explore the cranium and mandible morphology of a known hybrid (NHMD MCE 1356) and the cranium morphology of a putative hybrid (NHMD 1963.44.1.4) relative to skull morphological variation in the parental species. Specifically, we used 3D models of skulls from 69 belugas, 86 narwhals, and the two known/putative hybrids and 2D left hemi-mandibles from 20 belugas, 64 narwhals and the known hybrid. Skull shape analyses allowed clear discrimination between species. Narwhals are characterised by a relatively short rostrum and wide neurocranium while belugas show a more elongated and narrower cranium. Sexual size dimorphism was detected in narwhals, with males larger than females, but no sexual shape dimorphism was detected in either species (excluding presence/absence of tusks in narwhals). Morphological skull variation was also dependent on different allometric slopes between species and sexes in narwhals. Our analyses showed that the cranium of the known hybrid was phenotypically close to belugas but its 2D hemi-mandible had a narwhal shape and size morphology. Both cranium and mandible were strongly correlated, with the pattern of covariation being similar to belugas. The putative hybrid was a pure male narwhal with extruded teeth. Comparison of genomic DNA supported this result, and stable carbon and nitrogen isotope values suggested that the putative hybrid had a more benthic foraging strategy compared to narwhals. This work demonstrates that although the known hybrid could be discriminated from narwhals and belugas, detection of its affinities with these parental species was dependent on the part of the skull analysed., Competing Interests: The authors have declared that no competing interests exist.

Morphological, functional, and behavioral adaptations of bats are among the most diverse within mammals. A strong association between bat skull morphology and feeding behavior has been suggested previously. However, morphological variation related to other drivers of adaptation, in particular echolocation, remains understudied. We assessed variation in skull morphology with respect to ecology (diet and emission type) and function (bite force, masticatory muscles and echolocation characteristics) using geometric morphometrics and comparative methods. Our study suggests that variation in skull shape of 10 bat families is the result of adaptations to broad dietary categories and sound emission types (oral or nasal). Skull shape correlates with echolocation parameters only in a subsample of insectivorous species, possibly because they (almost) entirely rely on this sensory system for locating and capturing prey. Insectivores emitting low frequencies are characterized by a ventrally tilted rostrum, a trait not associated with feeding parameters. This result questions the validity of a trade-off between feeding and echolocation function. Our study advances understanding of the relationship between skull morphology and specific features of echolocation and suggests that evolutionary constraints due to echolocation may differ between different groups within the Chiroptera., (© 2021 The Authors. Integrative Zoology published by International Society of Zoological Sciences, Institute of Zoology/Chinese Academy of Sciences and John Wiley & Sons Australia, Ltd.)

Objective: White men in U.S. cultures of honor die by suicide at greater rates than other demographic groups. This finding has been attributed to factors such as the prevalence and use of firearms in men's suicide in honor states, as well as motivational risk factors (e.g., thwarted belongingness). Other features of honor cultures (e.g., physical aggression, risk-taking behaviors) suggest that honor-endorsing men may frequently experience painful and provocative events (PPEs), which, in turn, may facilitate practical capability for suicide. The present work tested this hypothesis and honor ideology's relationship to firearm ownership and storage practices., Method: In two samples of mostly White U.S. men-one undergraduate sample (N = 472, M age  = 19.76) and one middle- to older adult sample (N = 419, M age  = 65.17)-we assessed honor ideology endorsement, PPEs, practical capability for suicide, and firearm-related outcomes., Results: Honor endorsement was greater among firearm owners (particularly self-protective owners), but it was unrelated to storage practices. Honor endorsement was positively associated with PPEs and practical capability. Additionally, the relationship between honor ideology and practical capability was indirectly explained by PPE exposure., Conclusions: Results highlight multiple avenues-PPEs, practical capability for suicide, (self-protective) firearm ownership-by which masculine honor norms may place men at risk for suicide., (© 2021 The American Association of Suicidology.)

Genomic divergence was studied in 10 small insular populations of the endangered Balearic Islands lizard (Podarcis lilfordi) using double digest restriction-site associated DNA sequencing. The objectives were to establish levels of divergence among populations, investigate the impact of population size on genetic variability and to evaluate the role of different environmental factors on local adaptation. Analyses of 72,846 SNPs supported a highly differentiated genetic structure, being the populations with the lowest population size (Porros, Foradada and Esclatasang islets) the most divergent, indicative of greater genetic drift. Outlier tests identified ~ 2% of loci as candidates for selection. Genomic divergence-Enviroment Association analyses were performed using redundancy analyses based on SNPs putatively under selection, detecting predation and human pressure as the environmental variables with the greatest explanatory power. Geographical distributions of populations and environmental factors appear to be fundamental drivers of divergence. These results support the combined role of genetic drift and divergent selection in shaping the genetic structure of these endemic island lizard populations.

Reintroductions are a powerful tool for the recovery of endangered species. However, their long-term success is strongly influenced by the genetic diversity of the reintroduced population. The chances of population persistence can be improved by enhancing the population's adaptive ability through the mixing of individuals from different sources. However, where source populations are too diverse the reintroduced population could also suffer from outbreeding depression or unsuccessful admixture due to behavioural or genetic barriers. For the reintroduction of Asiatic wild ass Equus hemionus ssp. in Israel, a breeding core was created from individuals of two different subspecies ( E. h. onager & E. h. kulan ). Today the population comprises approximately 300 individuals and displays no signs of outbreeding depression. The aim of this study was a population genomic evaluation of this conservation reintroduction protocol. We used maximum likelihood methods and genetic clustering analyses to investigate subspecies admixture and test for spatial autocorrelation based on subspecies ancestry. Further, we analysed heterozygosity and effective population sizes in the breeding core prior to release and the current wild population. We discovered high levels of subspecies admixture in the breeding core and wild population, consistent with a significant heterozygote excess in the breeding core. Furthermore, we found no signs of spatial autocorrelation associated with subspecies ancestry in the wild population. Inbreeding and variance effective population size estimates were low. Our results indicate no genetic or behavioural barriers to admixture between the subspecies and suggest that their hybridization has led to greater genetic diversity in the reintroduced population. The study provides rare empirical evidence of the successful application of subspecies hybridization in a reintroduction. It supports use of intraspecific hybridization as a tool to increase genetic diversity in conservation translocations., Competing Interests: None declared., (© 2021 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

Imminent death donation (IDD) is described as living organ donation prior to a planned withdrawal of life-sustaining care in an imminently dying patient. Although IDD was ethically justified by United Network for Organ Sharing, the concept remains controversial due to presumed lack of public support. The aim of this study was to evaluate the public's attitudes towards IDD. A cross-sectional survey was conducted of US adults age >18 years (n = 2644). The survey included a case scenario of a patient with a devastating brain injury. Responses were assessed on a 5-point Likert scale. Results showed that 68% - 74% of participants agreed or strongly agreed with IDD when posed as a general question and in relation to the case scenario. Participants were concerned about "recovery after a devastating brain injury" (34%), and that "doctors would not try as hard to save a patient's life" (33%). Only 9% of participants would be less likely to trust the organ donation process. In conclusion, our study demonstrates strong public support for IDD in the case of a patient with a devastating brain injury. Notably, participants were not largely concerned with losing trust in the organ donation process. These results justify policy change towards imminent death donation., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Identification of the role of the MC1R gene has provided major insights into variation in skin pigmentation in several organisms, including humans, but the evolutionary genetics of this variation is less well established. Variation in this gene and its relationship with degree of melanism was analyzed in one of the world's highest-elevation lizards, Phrynocephalus theobaldi from the Qinghai-Tibetan Plateau. Individuals from the low-elevation group were shown to have darker dorsal pigmentation than individuals from a high-elevation group. The existence of climatic variation across these elevations was quantified, with lower elevations exhibiting higher air pressure, temperatures, and humidity, but less wind and insolation. Analysis of the MC1R gene in 214 individuals revealed amino acid differences at five sites between intraspecific sister lineages from different elevations, with two sites showing distinct fixed residues at low elevations. Three of the four single-nucleotide polymorphisms that underpinned these amino acid differences were highly significant outliers, relative to the generalized MC1R population structuring, suggestive of selection. Transfection of cells with an MC1R allele from a lighter high-elevation population caused a 43% reduction in agonist-induced cyclic AMP accumulation, and hence lowered melanin synthesis, relative to transfection with an allele from a darker low-elevation population. The high-elevation allele led to less efficient integration of the MC1R protein into melanocyte membranes. Our study identifies variation in the degree of melanism that can be explained by four or fewer MC1R substitutions. We establish a functional link between these substitutions and melanin synthesis and demonstrate elevation-associated shifts in their frequencies., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Aims: Identify the attitudes and interests of primary care providers (PCPs) in applying clinical pharmacogenomics (PGx) test results. Materials & methods: A questionnaire was designed and then disseminated to PCPs across the MedStar Health System. Results: Ninety of 312 (29%) PCPs responded and were included in analyses. Seventy-six (84%) had heard of PGx and 12 (13%) previously ordered PGx testing. Most, 68 (76%), believed PGx can improve care; however, a minority, 23 (26%), reported confidence in using PGx in prescribing decisions. Sixty-four (70%) wanted a pharmacist consultation. PCPs desired PGx for antidepressants (75%), proton pump inhibitors (72%) and other medications. Conclusion: Most PCPs felt unprepared to interpret PGx results and desired pharmacist consultations. These data can inform future PGx implementations with PCPs.

Background: The clonoSEQ® Assay (Adaptive Biotechnologies Corporation, Seattle, USA) identifies and tracks unique disease-associated immunoglobulin (Ig) sequences by next-generation sequencing of IgH, IgK, and IgL rearrangements and IgH-BCL1/2 translocations in malignant B cells. Here, we describe studies to validate the analytical performance of the assay using patient samples and cell lines., Methods: Sensitivity and specificity were established by defining the limit of detection (LoD), limit of quantitation (LoQ) and limit of blank (LoB) in genomic DNA (gDNA) from 66 patients with multiple myeloma (MM), acute lymphoblastic leukemia (ALL), or chronic lymphocytic leukemia (CLL), and three cell lines. Healthy donor gDNA was used as a diluent to contrive samples with specific DNA masses and malignant-cell frequencies. Precision was validated using a range of samples contrived from patient gDNA, healthy donor gDNA, and 9 cell lines to generate measurable residual disease (MRD) frequencies spanning clinically relevant thresholds. Linearity was determined using samples contrived from cell line gDNA spiked into healthy gDNA to generate 11 MRD frequencies for each DNA input, then confirmed using clinical samples. Quantitation accuracy was assessed by (1) comparing clonoSEQ and multiparametric flow cytometry (mpFC) measurements of ALL and MM cell lines diluted in healthy mononuclear cells, and (2) analyzing precision study data for bias between clonoSEQ MRD results in diluted gDNA and those expected from mpFC based on original, undiluted samples. Repeatability of nucleotide base calls was assessed via the assay's ability to recover malignant clonotype sequences across several replicates, process features, and MRD levels., Results: LoD and LoQ were estimated at 1.903 cells and 2.390 malignant cells, respectively. LoB was zero in healthy donor gDNA. Precision ranged from 18% CV (coefficient of variation) at higher DNA inputs to 68% CV near the LoD. Variance component analysis showed MRD results were robust, with expected laboratory process variations contributing ≤3% CV. Linearity and accuracy were demonstrated for each disease across orders of magnitude of clonal frequencies. Nucleotide sequence error rates were extremely low., Conclusions: These studies validate the analytical performance of the clonoSEQ Assay and demonstrate its potential as a highly sensitive diagnostic tool for selected lymphoid malignancies.

Most literature describing pharmacogenetic implementations are within academic medical centers and use single-gene tests. Our objective was to describe the results and lessons learned from a multisite pharmacogenetic pilot that utilized panel-based testing in academic and nonacademic settings. This was a retrospective analysis of 667 patients from a pilot in 4 perioperative and 5 outpatient cardiology clinics. Recommendations related to 12 genes and 65 drugs were classified as actionable or not actionable. They were ascertained from Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines and US Food and Drug Administration (FDA) labeling. Patients displayed a high prevalence of actionable results (88%, 99%) and use of medications (28%, 46%) with FDA or CPIC recommendations, respectively. Sixteen percent of patients had an actionable result for a current medication per CPIC compared with 5% per FDA labeling. A systematic approach by a health system may be beneficial given the quantity and diversity of patients affected., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Objective: To determine if a 12-week yoga intervention (YI) was associated with increased gamma aminobutyric acid (GABA) levels and decreased depressive symptoms in participants with major depressive disorder (MDD). Methods : Subjects were randomized to a high-dose group (HDG) of three YIs a week and a low-dose group (LDG) of two YIs a week. Thalamic GABA levels were obtained using magnetic resonance spectroscopy at Scan-1 before randomization. After the assigned 12-week intervention, Scan-2 was obtained, immediately followed by a YI and Scan-3. Beck Depression Inventory II (BDI-II) scores were obtained before Scan-1 and Scan-3. Settings/Location: Screenings and interventions occurred at the Boston University Medical Center. Imaging occurred at McLean Hospital. Subjects: Subjects met criteria for MDD. Intervention: Ninety minutes of Iyengar yoga and coherent breathing at five breaths per minute plus homework. Outcome measures: GABA levels and the BDI-II. Results: BDI-II scores improved significantly in both groups. GABA levels from Scan-1 to Scan-3 and from Scan-2 to Scan-3 were significantly increased in the LDG ( n  = 15) and showed a trend in the total cohort. Post hoc , participants were divided into two groups based on having an increase in GABA levels at Scan-2. Increases in Scan-2 GABA levels were observed in participants whose mean time between their last YI and Scan-2 was 3.93 ± 2.92 standard deviation (SD) days, but not in those whose mean time between their last YI and Scan-2 was 7.83 ± 6.88 SD. Conclusions: This study tentatively supports the hypothesis that one of the mechanisms through which yoga improves mood is by increasing the activity of the GABA system. The observed increase in GABA levels following a YI that was no longer observed 8 days after a YI suggests that the associated increase in GABA after a YI is time limited such that at least one YI a week may be necessary to maintain the elevated GABA levels.

Background: Evidence suggests that yoga may be an effective treatment for major depressive disorder (MDD). Studies evaluating the "dosing" of yoga treatment and efficacy for MDD are needed. The goal of this study was to assess the effects of an intervention combining Iyengar yoga and coherent breathing in participants with MDD and determine the optimal intervention dose., Methods: Thirty-two participants (18 to 65 y of age) diagnosed with MDD were randomized to a high-dose group (HDG) or a low-dose group (LDG) of yoga and coherent breathing for 12 weeks. The HDG (n=15) involved three 90-minute yoga classes and four 30-minute homework sessions per week. The LDG (n=15) involved two 90-minute yoga classes and three 30-minute homework sessions per week. Participants were evaluated at baseline, week 4, week 8, and week 12 with the following instruments: Positivity Self-Test, Spielberger State Anxiety Inventory, Patient Health Questionnaire-9, Pittsburgh Sleep Quality Index, and Exercise-induced Feeling Inventory. Data were analyzed using intent-to-treat methods., Results: Significant improvements in all outcome measures were found for both groups, with acute and cumulative benefits. Although the HDG showed greater improvements on all scales, between-group differences did not reach significance, possibly due to lack of power because of the small sample size. Cumulative yoga minutes were correlated with improvement in outcome measures., Limitation: This dosing study did not include a non-yoga control., Conclusions: Improvement in psychological symptoms correlated with cumulative yoga practice. Both interventions reduced symptoms of depression and anxiety and increased feelings of positivity. The time commitment for yoga practice needs to be weighed against benefits when designing yoga interventions.

Many species have been established on the basis of morphology, with markers such as mtDNA used to confirm the existence of independent historical lineages. Discordance between morphology and gene trees makes this less straightforward. Genotyping by sequencing (GBS) was used to analyse general genomic divergence across two recognized high altitude lizard species found in the eastern Qinghai-Tibetan Plateau. One of the species (Phyrnocephalus guinanensis) is found on a large area of sand dune habitat and distinguished from the other (P. putjatia) by morphology. We found that the primary pattern of genomic divergence is discordant with these morphological species: northern P. putjatia populations from around the large saline Qinghai lake are genomically distinct from P. putjatia and P. guinanensis populations located south of the Qinghai South and Riyue Mountains. Two competing historical scenarios were assessed using approximate Bayesian computation which unequivocally favoured a split between populations separated by the Qinghai South and Riyue mountains over a split between morphological species. The findings indicate that historical vicariance due to geographical features underpins the phylogenetic split rather than ecology-mediated divergence between sand dune and non-sand areas which i) is predicted by the mtDNA tree (showing the utility of this marker in species delimitation) and ii) demonstrates the unsuitability of the morphology-based taxonomy (indicating that large morphological differences do not always reflect historical lineages). In addition, we found a clear signal of isolation-by-distance around the periphery of Qinghai lake which suggests: i) a high level of resolution by GBS for detecting local divergence and ii) restricted gene flow over relatively short geographic distances. Overall, we show how morphological variation can mislead taxonomic conclusions and the utility of GBS for resolving these issues., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Blood passage through medical devices can cause hemolysis and increased levels of plasma free hemoglobin (pfH) that may lead to adverse effects such as vasoconstriction and renal tubule injury. Although the hemolytic potential of devices is typically characterized in vitro using animal blood, the results can be impacted by various blood parameters, such as donor species. Moreover, it is unclear how to relate measured in vitro hemolysis levels to clinical performance because pfH accumulation in vivo depends on both hemolysis rate and availability of plasma haptoglobin (Hpt) that can bind and safely eliminate pfH. To help to address these uncertainties, we developed a biokinetic model linking in vivo hemolysis rates to time-dependent pfH and Hpt concentrations. The model was initially parameterized using studies that characterized baseline levels and evolution of pfH and Hpt after introduction of excess pfH in humans. With the biokinetic parameters specified, the model was applied to predict hemolysis rates in three patient groups undergoing cardiopulmonary bypass surgery. The congruity of the model with these clinical data suggests that it can infer in vivo hemolysis rates and provide insight into pfH levels that may cause concern. The model was subsequently used to evaluate acceptance threshold hemolysis values proposed in the literature for chronic circulatory assist blood pumps and to assess the impact of patient weight on pfH accumulation using simple scaling arguments, which suggested that identical hemolysis index values may increase pfH levels nearly threefold in 10 kg pediatric patients compared with 80 kg adults.

This study advances the chemical research community toward the goal of replacing toxic cadmium-containing quantum dots (QDs) with environmentally benign InP QDs. The InP QD synthesis uniquely combines the previously reported use of InP magic-sized clusters (MSCs) as a single-source precursor for indium and phosphorus to form InP QDs, with zinc incorporation and subsequent ZnS shelling, to form InPZn/ZnS QDs with luminescence properties comparable to those of commonly used cadmium-containing luminescent QDs. The resulting InPZn/ZnS QDs have an emission quantum yield of about 50% across a broad range of emission peak wavelengths and emission peaks averaging 50 nm fwhm. The emission peak wavelength can be easily tuned by varying the Zn/In ratio in the reaction mixture. The strategy of using zinc stearate to tune the emission properties is advantageous as it does not lead to a loss of emission quantum yield or emission peak broadening. Although the initial optical properties of InP and InPZn/ZnS QDs are promising, thermal stability measurements of InPZn QDs show significant degradation in the absence of a shell compared to the CdSe QDs particularly at increased temperature in the presence of oxygen, which is indicative of thermal oxidation. There is no significant difference in the degradation rate of InP QDs made from molecular precursors and from MSCs. Additionally, the emission intensity and quantum yield of InPZn/ZnS QDs when purified and diluted in organic solvents under ambient conditions decrease significantly compared to those of CdSe/ZnS QDs. This indicates instability of the ZnS shell when prepared by common literature methods. This must be improved to realize high-quality, robust Cd-free QDs with the capability of replacing CdSe QDs in QD technologies.

Plasma hemoglobin (Hb) is elevated in some hematologic disease states, during exposures to certain toxicants, and with the use of some medical devices. Exposure to free Hb can precipitate oxidative reactions within tissues and alter the normal physiological function of critical organ systems. As kidney structures can be highly sensitive to Hb exposures, we evaluated the acute dose dependent renal toxicologic response to purified Hb isolated from RBCs. Male Hartley guinea pigs (n = 5 per group) were dosed with 0.9% saline (2 ml), 15, 75, 150, or 300 mg of purified Hb, infused over a 2-h period. The primary endpoints of this study were to define toxicokinetic parameters after increasing doses of purified Hb, identify clinically recognized and experimental markers of acute kidney injury (AKI), and determine relevant toxicological parameters and potential causes of renal toxicity in this model. Experimental findings demonstrated a dose dependent increase in Cmax after a 2-h infusion, which correlated with an elevation in serum creatinine, renal Kim-1 mRNA expression and increased urinary Kim-1. Renal NGAL mRNA expression and urinary NGAL excretion were also increased in several groups, but these parameters did not correlate with exposure. Iron increased in the renal cortex as Hb exposure increased and its deposition colocalized with 4-hydroxy-nonenal and 8-Oxo-2-deoxyguanosine immune reactivity, suggesting oxidative stressors may contribute to AKI in animals exposed to Hb. The results presented here suggest that Cmax may effectively predict the risk of AKI in normal healthy animals exposed to Hb.

Cadmium-containing luminescent quantum dots (QD) are increasingly used in display, bioimaging, and energy technologies; however, significant concerns have been raised about their potentially adverse impact on human health and the environment. This study makes use of a broad toolkit of analytical methods to investigate and increase our understanding of the interactions of luminescent cadmium-containing (CdSe) and cadmium-free (ZnSe) QD, with and without a passivating higher bandgap energy ZnS shell, with phospholipid vesicles (liposomes), which model bacterial membranes, and with Shewanella oneidensis MR-1, an environmentally relevant bacteria. A unique feature of this study is that all QD types have the same surface chemistry, being capped with uncharged poly(ethylene glycol) ligands. This enables focusing the study on the impact of the QD core on liposomes and bacterial cells. The study reveals that QD association with liposome and bacterial cell membranes is imperative for their adverse impact on liposomes and bacterial cells. The QD' concentration-dependent association with liposomes and bacterial cells destabilizes the membranes mechanically, which leads to membrane disruption and lysis in liposomes and to bacterial cell death. The study also shows that cadmium-containing QD exhibit a higher level of membrane disruption in bacterial cells than cadmium-free QD. ZnSe QD have low membrane impact, and coating them with a ZnS shell decreases their membrane disruption activity. In contrast, CdSe QD exhibit a high level of membrane impact, and coating them with a ZnS shell does not decrease, but in fact further increases, their membrane disruption activity. This behavior might be attributed to higher affinity and association of CdSe/ZnS QD with liposomes and bacterial cells and to a contribution of dissolved zinc ions from the ZnS shell to increased membrane disruption activity., Competing Interests: The authors declare no competing financial interest.

Conclusions: The inherent tradeoff between sensitivity and specificity in the detection of unexplained antibodies has been the objective of many studies, editorials, and journal articles. Many publications note that no method is capable of detecting all clinically significant antibodies while avoiding all clinically insignificant antibodies. This study describes the frequency of nonspecific reactivity and unexplained reactivity in solid-phase testing, along with the subsequent development of specific antibodies (Abs). In this study, nonspecific reactivity (NS) is defined as method-specific panreactivity detected by solid-phase testing only, with no reactivity in other methods. Unexplained reactivity (UR) is defined as reactivity present and detectable in all test methods after all clinically significant antibodies were ruled out following a standard antibody identification algorithm using selected cell panels. This retrospective study evaluated antibody detection tests of patients at a single center for 2 years using two automated solid-phase instruments that used the same three-cell antibody detection test. Antibody identification was performed with solid-phase panels supplemented with a polyethylene glycol tube method as needed. Of the 1934 (5%) samples with a positive antibody detection test, 29 had unavailable work-up data, leaving 1905 (98.5%) samples eligible for inclusion in the study. The data revealed the following: Ab only 999 (52.4%); UR only 429 (22.5%); Ab and UR 227 (11.9%); NS only 206 (10.8%); Ab and NS 24 (1.3%); UR and NS 14 (0.7%); and Ab, UR, and NS 6 (0.3%). Patients with a positive follow-up antibody detection test had UR and NS replaced with a specific Ab in 23 of 656 UR (3%) and 8 of 230 NS (3%) cases, respectively. Additionally, six patients with UR developed a specific Ab along with persistent UR, and no patients with persistent NS developed a specific Ab. The study concluded that both UR and NS can be encountered in solid-phase testing, and both UR and NS can persist in follow-up testing. Specific Ab was observed to replace UR in a few patients.

The non-venomous grass snake (Natrix helvetica) and the venomous adder (Vipera berus) are two native species that are often found in sympatry in Great Britain and Europe. They occupy partially overlapping ecological niches and prey on small vertebrates, but use different feeding strategies. Here, we investigated the morphologies of grass snakes and adders from Dorset (UK) using two-dimensional geometric morphometrics to assess the degree of sexual dimorphism in size and shape together with the relative impact of allometry and general body dimensions on head shape. Both species showed significant sexual dimorphism in head size, but not in head shape. We found a clear allometric pattern in N. helvetica, whereas allometry in V. berus was generally less pronounced. Body dimensions were strongly correlated with head shape in the grass snake, but not in the adder. The fact that V. berus is venomous appears to explain the lack of allometric patterns and the lack of an association between body dimensions and head shape. The high degree of size dimorphism identified in both species could originate from the advantages of reduced intraspecific competition that are conveyed by a partial differentiation in feeding morphology., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

As-synthesized malic acid carbon dots are found to possess photoblinking properties that are outstanding and superior compared to those of conventional dyes. Considering their excellent biocompatibility, malic acid carbon dots are suitable for super-resolution fluorescence localization microscopy under a variety of conditions, as we demonstrate in fixed and live trout gill epithelial cells. In addition, during imaging experiments, the so-called "excitation wavelength-dependent" emission was not observed for individual as-made malic acid carbon dots, which motivated us to develop a time-saving and high-throughput separation technique to isolate malic acid carbon dots into fractions of different particle size distributions using C 18 reversed-phase silica gel column chromatography. This post-treatment allowed us to determine how particle size distribution influences the optical properties of malic acid carbon dot fractions, that is, optical band gap energies and photoluminescence behaviors.

Many cardiovascular device alloys contain nickel, which if released in sufficient quantities, can lead to adverse health effects. However, in-vivo nickel release from implanted devices and subsequent biodistribution of nickel ions to local tissues and systemic circulation are not well understood. To address this uncertainty, we have developed a multi-scale (material, tissue, and system) biokinetic model. The model links nickel release from an implanted cardiovascular device to concentrations in peri-implant tissue, as well as in serum and urine, which can be readily monitored. The model was parameterized for a specific cardiovascular implant, nitinol septal occluders, using in-vitro nickel release test results, studies of ex-vivo uptake into heart tissue, and in-vivo and clinical measurements from the literature. Our results show that the model accurately predicts nickel concentrations in peri-implant tissue in an animal model and in serum and urine of septal occluder patients. The congruity of the model with these data suggests it may provide useful insight to establish nickel exposure limits and interpret biomonitoring data. Finally, we use the model to predict local and systemic nickel exposure due to passive release from nitinol devices produced using a wide range of manufacturing processes, as well as general relationships between release rate and exposure. These relationships suggest that peri-implant tissue and serum levels of nickel will remain below 5 μg/g and 10 μg/l, respectively, in patients who have received implanted nitinol cardiovascular devices provided the rate of nickel release per device surface area does not exceed 0.074 μg/(cm 2  d) and is less than 32 μg/d in total., Statement of Significance: The uncertainty in whether in-vitro tests used to evaluate metal ion release from medical products are representative of clinical environments is one of the largest roadblocks to establishing the associated patient risk. We have developed and validated a multi-scale biokinetic model linking nickel release from cardiovascular devices in-vivo to both peri-implant and systemic levels. By providing clinically relevant exposure estimates, the model vastly improves the evaluation of risk posed to patients by the nickel contained within these devices. Our model is the first to address the potential for local and systemic metal ion exposure due to a medical device and can serve as a basis for future efforts aimed at other metal ions and biomedical products., (Published by Elsevier Ltd.)

Prior research has connected the cultural ideology of honor to intrasexual violence between men and to attitudes supporting intersexual aggression in response to perceived honor violations by female romantic partners. We extend this research to show that honor ideology is also associated with an increased likelihood of men actually engaging in violent and sexually coercive behaviors toward women. Extending previous research on honor-based schemas and scripts linked to relationship violence, comparisons between honor states and non-honor states in the United States show that official rape and domestic homicide rates by White male perpetrators (Study 1) and experiences of rape and violence in relationships anonymously reported by White female teenagers (Study 2) were higher in honor states, controlling for a variety of potential confounds. These results extend prior laboratory research on honor-based schemas and scripts into the realm of extreme, real-world behaviors.

Background: Yoga interventions offer promise for the treatment of major depressive disorder (MDD), yet their safety and potential impact on suicidal ideation (SI) have not been well documented. This study evaluated the safety of a randomized controlled dose-finding trial of Iyengar yoga plus coherent breathing for individuals with MDD, as well as the potential effects of the intervention on SI without intent., Methods: Participants with Beck Depression Inventory-II (BDI-II) scores ≥14 and a diagnosis of MDD (using DSM-IV criteria) were randomized to either a low dose group (LDG) or high dose group (HDG) and received a 12-week manualized intervention. The LDG included two 90-min yoga classes plus three 30-min homework sessions weekly. The HDG offered three 90-min classes plus four 30-min homework sessions weekly., Results: Thirty-two individuals with MDD were randomized, of which 30 completed the protocol. At screening, SI without intent was endorsed on the BDI-II by 9 participants; after completing the intervention, 8 out of 9 reported resolution of SI. There were 17 adverse events possibly-related and 15 definitely-related to the intervention. The most common protocol-related adverse event was musculoskeletal pain, which resolved over the course of the study., Conclusions: The Iyengar yoga plus coherent breathing intervention was associated with the resolution of SI in 8 out of 9 participants, with mild side effects that were primarily musculoskeletal in nature. This preliminary evidence suggests that this intervention may reduce SI without intent and be safe for use in those with MDD., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Animals living at high altitude must adapt to environments with hypoxia and low temperatures, but relatively little is known about underlying genetic changes. Toad-headed lizards of the genus Phrynocephalus cover a broad altitudinal gradient of over 4000 m and are useful models for studies of such adaptive responses. In one of the first studies to have considered selection on mitochondrial protein-coding regions in an ectothermic group distributed over such a wide range of environments, we analysed nineteen complete mitochondrial genomes from all Chinese Phrynocephalus (including eight genomes sequenced for the first time). Initial analyses used site and branch-site model (program: PAML) approaches to examine nonsynonymous: synonymous substitution rates across the mtDNA tree., Results: Ten positively selected sites were discovered, nine of which corresponded to subunits ND2, ND3, ND4, ND5, and ND6 within the respiratory chain enzyme mitochondrial Complex I (NADH Coenzyme Q oxidoreductase). Four of these sites showed evidence of general long-term selection across the group while the remainder showed evidence of episodic selection across different branches of the tree. Some of these branches corresponded to increases in altitude and/or latitude. Analyses of physicochemical changes in protein structures revealed that residue changes at sites that were under selection corresponded to major functional differences. Analyses of coevolution point to coevolution of selected sites within the ND4 subunit, with key sites associated with proton translocation across the mitochondrial membrane., Conclusions: Our results identify mitochondrial Complex I as a target for environment-mediated selection in this group of lizards, a complex that frequently appears to be under selection in other organisms. This makes these lizards good candidates for more detailed future studies of molecular evolution.

Objective: A systematic review on S-adenosylmethionine (SAMe) for treatment of neuropsychiatric conditions and comorbid medical conditions., Data Sources: Searches were conducted in PubMed, EMBASE, PsycINFO, Cochrane Library, CINAHL, and Google Scholar databases between July 15, 2015, and September 28, 2016, by combining search terms for SAMe (s-adenosyl methionine or s-adenosyl-l-methionine) with terms for relevant disease states (major depressive disorder, MDD, depression, perinatal depression, human immunodeficiency virus, HIV, Parkinson's, Alzheimer's, dementia, anxiety, schizophrenia, psychotic, 22q11.2, substance abuse, fibromyalgia, osteoarthritis, hepatitis, or cirrhosis). Additional studies were identified from prior literature. Ongoing clinical trials were identified through clinical trial registries., Study Selection: Of the 174 records retrieved, 21 were excluded, as they were not original investigations. An additional 21 records were excluded for falling outside the scope of this review. Of the 132 studies included in this review, 115 were clinical trials and 17 were preclinical studies., Data Extraction: A wide range of studies was included in this review to capture information that would be of interest to psychiatrists in clinical practice., Results: This review of SAMe in the treatment of major depressive disorder found promising but limited evidence of efficacy and safety to support its use as a monotherapy and as an augmentation for other antidepressants. Additionally, preliminary evidence suggests that SAMe may ameliorate symptoms in certain neurocognitive, substance use, and psychotic disorders and comorbid medical conditions., Conclusions: S-adenosylmethionine holds promise as a treatment for multiple neuropsychiatric conditions, but the body of evidence has limitations. The encouraging findings support further study of SAMe in both psychiatric and comorbid medical illnesses., (© Copyright 2017 Physicians Postgraduate Press, Inc.)

The Qinghai-Tibetan Plateau (QTP) represents one of the earth's most significant physical features and there is increasing interest in the historical generation of biodiversity within this region. We hypothesized that there should be clear geographically coherent genetic structuring within one of the world's highest altitude lizards, Phrynocephalus theobaldi, due to considerable historical population fragmentation in this environment. This was tested using a major mitochondrial DNA (mtDNA) survey and sequencing of two nuclear markers (AME and RAG-1) from P. theobaldi, from across the southern QTP. A Bayesian method (BPEC) was used to detect four geographically structured mtDNA clusters. A Bayesian phylogenetic tree, together with associated dating analyses, supported four corresponding evolutionary lineages with a timing of 3.74-7.03 Ma for the most basal P. theobaldi split and Pliocene splits of 2.97-5.79 Ma and 2.40-5.39 Ma in the two daughter lineages. Himalayan uplift and changes in the Jilong basin may have contributed to these divergences, but uplift of the Gangdese mountains is rejected due to its timing. The nuclear markers appeared to be sorted between the four mtDNA groups, and species delimitation analyses supported the four phylogeographical groups as candidate species. The study contributes to our understanding of biodiversity on the QTP.

Silver nanoparticles (AgNP) are incorporated into medical devices for their anti-microbial characteristics. The potential exposure and toxicity of AgNPs is unknown due to varying physicochemical particle properties and lack of toxicological data. The aim of this safety assessment is to derive a provisional tolerable intake (pTI) value for AgNPs released from blood-contacting medical devices. A literature review of in vivo studies investigating critical health effects induced from intravenous (i. v.) exposure to AgNPs was evaluated by the Annapolis Accords principles and Toxicological Data Reliability Assessment Tool (ToxRTool). The point of departure (POD) was based on an i. v. 28-day repeated AgNP (20 nm) dose toxicity study reporting an increase in relative spleen weight in rats with a 5% lower confidence bound of the benchmark dose (BMDL 05 ) of 0.14 mg/kg bw/day. The POD was extrapolated to humans by a modifying factor of 1,000 to account for intraspecies variability, interspecies differences and lack of long-term toxicity data. The pTI for long-term i. v. exposure to 20 nm AgNPs released from blood-contacting medical devices was 0.14 μg/kg bw/day. This pTI may not be appropriate for nanoparticles of other physicochemical properties or routes of administration. The methodology is appropriate for deriving pTIs for nanoparticles in general., (Published by Elsevier Inc.)

Silver nanoparticles (AgNPs) have generated a great deal of interest in the research, consumer product, and medical product communities due to their antimicrobial and anti-biofouling properties. However, in addition to their antimicrobial action, concerns have been expressed about the potential adverse human health effects of AgNPs. In vitro cytotoxicity studies often are used to characterize the biological response to AgNPs and the results of these studies may be used to identify hazards associated with exposure to AgNPs. Various factors, such as nanomaterial size (diameter), surface area, surface charge, redox potential, surface functionalization, and composition play a role in the development of toxicity in in vitro test systems. In addition, the interference of AgNPs with in vitro cytotoxicity assays may result in false negative or false positive results in some in vitro biological tests. The goal of this review is to: 1) summarize the impact of physical-chemical parameters, including size, shape, surface chemistry and aggregate formation on the in vitro cytotoxic effects of AgNPs; and 2) explore the nature of AgNPs interference in in vitro cytotoxicity assays., (Published by Elsevier Ltd.)

Background: Podarcis tiliguerta is a wall lizard endemic to the Mediterranean islands of Corsica and Sardinia. Previous findings of high mtDNA and morphological diversity have led to the suggestion that it may represent a species complex. Here, we analysed mitochondrial and nuclear markers (mtDNA, 3110 bp; 6 nDNA loci, 3961 bp) in P. tiliguerta sampled from thirty-two localities across Corsica and Sardinia., Results: We find much greater intraspecific genetic divergence than between sister species of other Mediterranean island Podarcis, i.e., between P. lilfordi and P. pityusensis. We detected three mtDNA clusters in Corsica (North, South-East and South-West) and either two or three in Sardinia (North vs. South) depending on the clustering method. Only one or two nDNA groups were identified within each main island (again, depending on the method). A Bayesian time-calibrated multispecies coalescent tree was obtained from mtDNA and provided statistical support for a Miocene origin of the species (13.87 Ma, 95% HPD: 18.30-10.77 Ma). The posterior mean divergence time for the Corsican and Sardinian lineages was 12.75 Ma ago (95% HPD: 16.94-9.04 Ma)., Conclusion: The results support the evolutionary distinctiveness of Corsican and Sardinian populations and also indicate a lack of post-divergence migration despite periods of contact being possible. Further to this, species delimitation analyses of Corsican and Sardinian lineages provided statistical support for their recognition as distinct (sister) taxa. Our results provide new insights into the biogeography of the Mediterranean biodiversity hotspot, and contribute important findings relevant to the systematics and evolution of this speciose lizard genus.

Geographical variation among contiguous populations is frequently attributed to ecological divergence or historical isolation followed by secondary contact. Distinguishing between these effects is key to studies of incipient speciation and could be revealed by different genomic signatures. We used RAD-seq analyses to examine morphologically divergent populations of the endemic lizard (Gallotia galloti) from the volcanic island of Tenerife. Previous analyses have suggested ecological and historical causes to explain the morphological diversity. Analyses of 276,483 single nucleotide polymorphisms (SNPs) from >20 Mbp of the genome revealed one genetically divergent population from Anaga, a region associated with divergent mtDNA lineages in other Tenerife endemics. This population also has a high number of private alleles, and its divergence can be explained by historical isolation. Bayesian outlier analyses identified a small proportion of SNPs as candidates for selection (0.04%) which were strongly differentiated between xeric and mesic habitat types. Individual testing for specific xeric-mesic selection using an alternative approach also supported ecological divergence in a similarly small proportion of SNPs. The study indicates the roles of both historical isolation and ecological divergence in shaping genomic diversity in G. galloti However, north-south morphological divergence appears solely associated with the latter and likely involves a relatively small proportion of the genome., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Many alloys used in cardiovascular device applications contain high levels of nickel, which if released in sufficient quantities, can lead to adverse health effects. While nickel release from these devices is typically characterized through the use of in-vitro immersion tests, it is unclear if the rate at which nickel is released from a device during in-vitro testing is representative of the release rate following implantation in the body. To address this uncertainty, we have developed a novel biokinetic model that combines a traditional toxicokinetic compartment model with a physics-based model to estimate nickel release from an implanted device. This model links the rate of in-vitro nickel release from a cardiovascular device to serum nickel concentrations, an easily measured endpoint, to estimate the rate and extent of in-vivo nickel release from an implanted device. The model was initially parameterized using data in the literature on in-vitro nickel release from a nickel-containing alloy (nitinol) and baseline serum nickel levels in humans. The results of this first step were then used to validate specific components of the model. The remaining unknown quantities were fit using serum values reported in patients following implantation with nitinol atrial occluder devices. The model is not only consistent with levels of nickel in serum and urine of patients following treatment with the atrial occluders, but also the optimized parameters in the model were all physiologically plausible. The congruity of the model with available data suggests that it can provide a framework to interpret nickel biomonitoring data and use data from in-vitro nickel immersion tests to estimate in-vivo nickel release from implanted cardiovascular devices., (Published by Elsevier Inc.)

Background: Menopausal women are challenged by the adverse effects of estrogen loss on energy, mood, cognitive function, and memory. These stresses are compounded by increased risks for cardiovascular disease, osteoporosis, and cancer. Known to have neuroprotective, cardio-protective, anti-oxidative and anti-carcinogenic effects, Rhodiola rosea extracts have also been shown to improve energy, mood, cognitive function and memory., Purpose: We propose that R. rosea be investigated for use as a potential selective estrogen receptor modulator (SERM) in the prevention and treatment of menopause-related fatigue, stress, depression, cognitive decline, memory impairment, cardiovascular disease, osteoporosis and cancer., Method: This paper briefly reviews the relationship between estrogen decline and menopause-related health risks, the molecular mechanisms underlying estrogenic effects on health, and the evidence indicating beneficial effects of R. rosea extracts on these mechanisms and health risks. Mechanisms include non-genomic and genomic effects, for example: activation of intra-cellular signal transduction pathways by binding to estrogen receptors, ERα-mediated activation of endothelial nitric oxide synthase with increased nitric oxide release; and anti-inflammatory effects, counteracting TNFα by inhibiting nuclear factor-Kappa-B (NF-KB) and protection of osteoblasts from hydrogen peroxide. A clinical case illustrating treatment of a menopausal woman with R. rosea is presented. Risks, benefits, gaps in knowledge, and future directions are discussed., Conclusion: Numerous lines of evidence indicate that R. rosea should be investigated as a potential selective estrogen receptor modulator (SERM) to prevent, delay or mitigate menopause-related cognitive, psychological, cardiovascular and osteoporotic conditions., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Background: This study evaluated the effects of the Breath-Body-Mind Workshop (BBMW) (breathing, movement, and meditation) on psychological and physical symptoms and inflammatory biomarkers in inflammatory bowel disease (IBD)., Methods: Twenty-nine IBD patients from the Jill Roberts IBD Center were randomized to BBMW or an educational seminar. Beck Anxiety Inventory, Beck Depression Inventory, Brief Symptom Inventory 18, IBD Questionnaire, Perceived Disability Scale, Perceived Stress Questionnaire, Digestive Disease Acceptance Questionnaire, Brief Illness Perception Questionnaire, fecal calprotectin, C-reactive protein, and physiological measures were obtained at baseline and weeks 6 and 26., Results: The BBMW group significantly improved between baseline and week 6 on Brief Symptom Inventory 18 (P = 0.02), Beck Anxiety Inventory (P = 0.02), and IBD Questionnaire (P = 0.01) and between baseline and week 26 on Brief Symptom Inventory 18 (P = 0.04), Beck Anxiety Inventory (P = 0.03), Beck Depression Inventory (P = 0.01), IBD Questionnaire (P = 0.01), Perceived Disability Scale (P = 0.001), and Perceived Stress Questionnaire (P = 0.01) by paired t tests. No significant changes occurred in the educational seminar group at week 6 or 26. By week 26, median C-reactive protein values decreased significantly in the BBMW group (P = 0.01 by Wilcoxon signed-rank test) versus no significant change in the educational seminar group., Conclusions: In patients with IBD, participation in the BBMW was associated with significant improvements in psychological and physical symptoms, quality of life, and C-reactive protein. Mind-body interventions, such as BBMW, which emphasize Voluntarily Regulated Breathing Practices, may have significant long-lasting benefits for IBD symptoms, anxiety, depression, quality of life, and inflammation. BBMW, a promising adjunctive treatment for IBD, warrants further study.

We examine a key modified labeling theory proposition-that a psychiatric label increases vulnerability to competence-based criticism and rejection-within task- and collectively oriented dyads comprised of same-sex individuals with equivalent education. Drawing on empirical work that approximates these conditions, we expect the proposition to hold only among men. We also expect education, operationalized with college class standing, to moderate the effects of gender by reducing men's and increasing women's criticism and rejection. But, we also expect the effect of education to weaken when men work with a psychiatric patient. As predicted, men reject suggestions from teammates with a psychiatric history more frequently than they reject suggestions from other teammates, while women's resistance to influence is unaffected by their teammate's psychiatric status. Men also rate psychiatric patient teammates as less powerful but no lower in status than other teammates, while women's teammate assessments are unaffected by their teammate's psychiatric status. Also as predicted, education reduces men's resistance to influence when their teammate has no psychiatric history. Education also increases men's ratings of their teammate's power, as predicted, but has no effect on women's resistance to influence or teammate ratings. We discuss the implications of these findings for the modified labeling theory of mental illness and status characteristics theory., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Complementary and alternative medicine (CAM) in psychiatry or integrative psychiatry covers a wide range of biological, psychological and mind-body treatments that enhance standard medical practices and patient outcomes. While CAM approaches are popular amongst patients in their practice as well as in self-report because of their ease of use, health professionals have received limited education in these interventions and often are unaware of their patients' use of CAM treatments., Method: This overview highlights evidence-based CAM treatments for attention deficit hyperactivity disorder (ADHD) including dietary interventions, phytomedicines, mind-body practices and neurofeedback., Results: While conventional treatments are the mainstays for ADHD, there are a large number of available treatments that can be used to enhance treatment response., Conclusion: With improved education and further scientific and clinical research, validated integrative treatments will provide more effective, lower risk and lower cost care for patients with ADHD.

Introduction. Complementary and alternative medicine (CAM) is frequently used by Parkinson's disease (PD) patients. We sought to provide information on CAM use and efficacy in PD patients in the Denver metro area with particular attention to cannabis use given its recent change in legal status. Methods. Self-administered surveys on CAM use and efficacy were completed by PD patients identified in clinics and support groups across the Denver metro area between 2012 and 2013. Results. 207 patients (age 69 ± 11; 60% male) completed the survey. Responses to individual CAM therapy items showed that 85% of respondents used at least one form of CAM. The most frequently reported CAMs were vitamins (66%), prayer (59%), massage (45%), and relaxation (32%). Self-reported improvement related to the use of CAM was highest for massage, art therapy, music therapy, and cannabis. While only 4.3% of our survey responders reported use of cannabis, it ranked among the most effective CAM therapies. Conclusions. Overall, our cross-sectional study was notable for a high rate of CAM utilization amongst PD patients and high rates of self-reported efficacy across most CAM modalities. Cannabis was rarely used in our population but users reported high efficacy, mainly for nonmotor symptoms.

Background: Parkinson disease (PD) may lead to functional limitations through both motor and nonmotor symptoms. Although patients with advanced disease have well-documented and profound functional limitations, less is known about the determinants of function in early to mid-stage disease where interventions may be more likely to benefit and preserve function., Objective: The objective of the current study was to identify motor, cognitive, and gait determinants of physical functional performance in patients with early to mid-stage PD., Design: This was a secondary analysis of cross-sectional baseline data from a randomized clinical trial of exercise., Setting: The study was performed at a tertiary academic medical center., Participants: The study included 121 patients with early to mid-stage PD., Methods: Our functional performance outcomes included the following: the Continuous Scale Physical Functional Performance Test (CS-PFP; primary outcome); the Timed Up and Go test (TUG); and Section 2 (Activities of Daily Living) of the Unified Parkinson's Disease Rating Scale (UPDRS). Explanatory variables included measures of disease severity, motor function, cognitive function, balance, and gait. Stepwise linear regression models were used to determine correlations between explanatory variables and outcome measures., Results: In our regression models, the CS-PFP significantly correlated with walking endurance (Six-Minute Walk Test; r(2) = 0.12, P < .0001), turning ability (360° Turn Test; r(2) = 0.03, P = .002), attention (Brief Test of Attention; r(2) = 0.01, P = .03), overall cognitive status (Mini-Mental State Examination; r(2) = 0.01, P = .04), and bradykinesia (timed tapping; r(2) = 0.02, P = .02). The TUG significantly correlated with walking speed (5-Meter Walk Test; r(2) = 0.33, P < .0001), stride length (r(2) = 0.25, P < .0001), turning ability (360° turn, r(2) = 0.05, P = .0003), and attention (r(2) = 0.016, P = .03). Section 2 of the UPDRS was significantly correlated with endurance (r(2) = 0.09, P < .0001), turning ability (r(2) = 0.03, P = .001), and attention (r(2) = 0.01, P = .03)., Conclusions: Gait, motor, and cognitive function all contribute to objectively measured global functional ability in mild to moderate PD. Subjectively measured functional activity outcomes may underestimate the impact of both motor and nonmotor symptoms., (Copyright © 2014 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.)

Population divergence and speciation are often explained by geographical isolation, but may also be possible under high gene flow due to strong ecology-related differences in selection pressures. This study combines coalescent analyses of genetic data (11 microsatellite loci and 1 Kbp of mtDNA) and ecological modelling to examine the relative contributions of isolation and ecology to incipient speciation in the scincid lizard Chalcides sexlineatus within the volcanic island of Gran Canaria. Bayesian multispecies coalescent dating of within-island genetic divergence of northern and southern populations showed correspondence with the timing of volcanic activity in the north of the island 1.5-3.0 Ma ago. Coalescent estimates of demographic changes reveal historical size increases in northern populations, consistent with expansions from a volcanic refuge. Nevertheless, ecological divergence is also supported. First, the two morphs showed non-equivalence of ecological niches and species distribution modelling associated the northern morph with mesic habitat types and the southern morph with xeric habitat types. It seems likely that the colour morphs are associated with different antipredator strategies in the different habitats. Second, coalescent estimation of gene copy migration (based on microsatellites and mtDNA) suggest high rates from northern to southern morphs demonstrating the strength of ecology-mediated selection pressures that maintain the divergent southern morph. Together, these findings underline the complexity of the speciation process by providing evidence for the combined effects of ecological divergence and ancient divergence in allopatry., (© 2014 John Wiley & Sons Ltd.)